tbuckley/cabot-search huggingface dataset:
Multimodality imaging and transcriptomics to phenotype mitral valve dystrophy in a unique knock-in Filamin-A rat model
Authors: Constance Delwarde, Claire Toquet, Pascal Aumond, Amir Hossein Kayvanjoo, Adrien Foucal, Benjamin Le Vely, Manon Baudic, Benjamin Lauzier, Stéphanie Blandin, Joëlle Véziers, Perrine Paul-Gilloteaux, Simon Lecointe, Estelle Baron, Ilaria Massaiu, Paolo Poggio, Séverine Rémy, Ignacio Anegon, Hervé Le Marec, Laurent Monassier, Jean-Jacques Schott, Elvira Mass, Julien Barc, Thierry Le Tourneau, Jean Merot, Romain Capoulade
Journal: Cardiovascular Research (2022)

Abstract Aims Degenerative mitral valve dystrophy (MVD) leading to mitral valve prolapse is the most frequent form of MV disease, and there is currently no pharmacological treatment available. The limited understanding of the pathophysiological mechanisms leading to MVD limits our ability to identify therapeutic targets. This study aimed to reveal the main pathophysiological pathways involved in MVD via the multimodality imaging and transcriptomic analysis of the new and unique knock-in (KI) rat model for the FilaminA-P637Q (FlnA-P637Q) mutation associated-MVD. Methods and results Wild-type (WT) and KI rats were evaluated morphologically, functionally, and histologically between 3-week-old and 3-to-6-month-old based on Doppler echocardiography, 3D micro-computed tomography (microCT), and standard histology. RNA-sequencing and Assay for Transposase-Accessible Chromatin (ATAC-seq) were performed on 3-week-old WT and KI mitral valves and valvular cells, respectively, to highlight the main signalling pathways associated with MVD. Echocardiographic exploration confirmed MV elongation (2.0 ± 0.1 mm vs. 1.8 ± 0.1, P = 0.001), as well as MV thickening and prolapse in KI animals compared to WT at 3 weeks. 3D MV volume quantified by microCT was significantly increased in KI animals (+58% vs. WT, P = 0.02). Histological analyses revealed a myxomatous remodelling in KI MV characterized by proteoglycans accumulation. A persistent phenotype was observed in adult KI rats. Signalling pathways related to extracellular matrix homeostasis, response to molecular stress, epithelial cell migration, endothelial to mesenchymal transition, chemotaxis and immune cell migration, were identified based on RNA-seq analysis. ATAC-seq analysis points to the critical role of transforming growth factor-β and inflammation in the disease. Conclusion The KI FlnA-P637Q rat model mimics human myxomatous MVD, offering a unique opportunity to decipher pathophysiological mechanisms related to this disease. Extracellular matrix organization, epithelial cell migration, response to mechanical stress, and a central contribution of immune cells are highlighted as the main signalling pathways leading to myxomatous MVD. Our findings pave the road to decipher underlying molecular mechanisms and the specific role of distinct cell populations in this context.
Retinol and Retinol Binding Protein 4 Levels and Cardiometabolic Disease Risk
Authors: Catarina Schiborn, Daniela Weber, Tilman Grune, Ronald Biemann, Susanne Jäger, Natascha Neu, Marie Müller von Blumencron, Andreas Fritsche, Cornelia Weikert, Matthias B. Schulze, Clemens Wittenbecher
Journal: Circulation Research (2022)

Despite mechanistic studies linking retinol and RBP4 (retinol binding protein 4) to the pathogenesis of cardiovascular diseases (CVD) and type 2 diabetes (T2D), epidemiological evidence is still conflicting. We investigated whether conflicting results of previous studies may be explained by differences in the association of retinol and RBP4 with cardiometabolic risk across subgroups with distinct sex, hypertension state, liver, or kidney function.We used case-cohorts nested in the EPIC (European Prospective Investigation Into Cancer and Nutrition)-Potsdam cohort (N=27 548) comprising a random sample of participants (n=2500) and all physician-verified cases of incident CVD (n=508, median follow-up time 8.2 years) and T2D (n=820, median follow-up time 6.3 years). We estimated nonlinear and linear multivariable-adjusted associations between the biomarkers and cardiometabolic diseases by restricted cubic splines and Cox regression, respectively, testing potential interactions with hypertension, liver, and kidney function. Additionally, we performed 2-sample Mendelian Randomization analyses in publicly available data.The association of retinol with cardiometabolic risk was modified by hypertension state (P interaction CVD<0.001; P interaction T2D<0.001). Retinol was associated with lower cardiometabolic risk in participants with treated hypertension (hazard ratioper SD [95% CI]: CVD, 0.71 [0.56-0.90]; T2D, 0.81 [0.70-0.94]) but with higher cardiometabolic risk in normotensive participants (CVD, 1.32 [1.06-1.64]; T2D, 1.15 [0.98-1.36]). Our analyses also indicated a significant interaction between RBP4 and hypertension on CVD risk (P interaction=0.04). Regarding T2D risk, we observed a u-shaped association with RBP4 in women (P nonlinearity=0.01, P effect=0.02) and no statistically significant association in men. The biomarkers' interactions with liver or kidney function were not statistically significant. Hypertension state-specific associations for retinol concentrations with cardiovascular mortality risk were replicated in National Health and Nutrition Examination Survey III.Our findings suggest a hypertension-dependent relationship between plasma retinol and cardiometabolic risk and complex interactions of RBP4 with sex and hypertension on cardiometabolic risk.
Development and validation of safety and efficacy-associated risk calculator for hepatocellular carcinoma in the elderly after resection (SEARCHER): A multi-institutional observational study
Authors: Zi-Xiang Chen, Myron Schwartz, Li-Hui Gu, Lei Liang, Ping Wang, Matteo Cescon, Ju-Dong Li, Ying-Jian Liang, Jia-Le Pu, Ya-Hao Zhou, Hong Wang, Wei-Min Gu, Ting-Hao Chen, Zhi-Yu Chen, Ming-Da Wang, Chao Li, Cheng-Wu Zhang, Timothy M. Pawlik, Wan Yee Lau, Feng Shen, Fu-Bao Liu, Tian Yang
Journal: International Journal of Surgery (2022)
Professional Civil Disobedience — Medical-Society Responsibilities after <i>Dobbs</i>
Authors: Matthew K Wynia
Journal: New England Journal of Medicine (2022)

www .immunizationforwomen .org) with up-to-date information for Ob/Gyns and works closely with the CDC's Advisory Committee on Immunization Practices to provide input on vaccine recommendations for pregnant people.These collaborative efforts facilitated the development and dissemination of recommendations related to Covid-19 diagnosis, treatment, and vaccination during pregnancy.Obstetric care providers will also need to be educated about climate change's effects on the health of their patients.Adding this content to medical school curricula, Ob/Gyn residency training, and maintenance-of-certification activities will help clinicians become more proficient in coun-seling patients about how to reduce their climate-change-associated risks and in advocating for addressing climate change and its health harms.Climate change is a major public health threat.National and global leaders need to urgently work together to limit the fossilfuel emissions that drive it.The effects of climate change are already threatening human health, however, and pregnant people and newborns are at especially high risk for related harm.Building on experience in preparing for and responding to emerging infectious diseases will be important to help minimize adverse effects in these and other vulnerable populations.The health of future generations depends on our actions today.
Nirmatrelvir Use and Severe Covid-19 Outcomes during the Omicron Surge
Authors: Ronen Arbel, Yael Wolff Sagy, Moshe Hoshen, Erez Battat, Gil Lavie, Ruslan Sergienko, Michael Friger, Jacob G. Waxman, Noa Dagan, Ran Balicer, Yatir Ben-Shlomo, Alon Peretz, Shlomit Yaron, Danielle Serby, Ariel Hammerman, Doron Netzer
Journal: New England Journal of Medicine (2022)

The oral protease inhibitor nirmatrelvir has shown substantial efficacy in high-risk, unvaccinated patients infected with the B.1.617.2 (delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Data regarding the effectiveness of nirmatrelvir in preventing severe coronavirus disease 2019 (Covid-19) outcomes from the B.1.1.529 (omicron) variant are limited.We obtained data for all members of Clalit Health Services who were 40 years of age or older at the start of the study period and were assessed as being eligible to receive nirmatrelvir therapy during the omicron surge. A Cox proportional-hazards regression model with time-dependent covariates was used to estimate the association of nirmatrelvir treatment with hospitalization and death due to Covid-19, with adjustment for sociodemographic factors, coexisting conditions, and previous SARS-CoV-2 immunity status.A total of 109,254 patients met the eligibility criteria, of whom 3902 (4%) received nirmatrelvir during the study period. Among patients 65 years of age or older, the rate of hospitalization due to Covid-19 was 14.7 cases per 100,000 person-days among treated patients as compared with 58.9 cases per 100,000 person-days among untreated patients (adjusted hazard ratio, 0.27; 95% confidence interval [CI], 0.15 to 0.49). The adjusted hazard ratio for death due to Covid-19 was 0.21 (95% CI, 0.05 to 0.82). Among patients 40 to 64 years of age, the rate of hospitalization due to Covid-19 was 15.2 cases per 100,000 person-days among treated patients and 15.8 cases per 100,000 person-days among untreated patients (adjusted hazard ratio, 0.74; 95% CI, 0.35 to 1.58). The adjusted hazard ratio for death due to Covid-19 was 1.32 (95% CI, 0.16 to 10.75).Among patients 65 years of age or older, the rates of hospitalization and death due to Covid-19 were significantly lower among those who received nirmatrelvir than among those who did not. No evidence of benefit was found in younger adults.
Identifying and correcting repeat-calling errors in nanopore sequencing of telomeres
Authors: Kar-Tong Tan, Michael K. Slevin, Matthew Meyerson, Heng Li
Journal: Genome biology (2022)

Abstract Nanopore long-read sequencing is an emerging approach for studying genomes, including long repetitive elements like telomeres. Here, we report extensive basecalling induced errors at telomere repeats across nanopore datasets, sequencing platforms, basecallers, and basecalling models. We find that telomeres in many organisms are frequently miscalled. We demonstrate that tuning of nanopore basecalling models leads to improved recovery and analysis of telomeric regions, with minimal negative impact on other genomic regions. We highlight the importance of verifying nanopore basecalls in long, repetitive, and poorly defined regions, and showcase how artefacts can be resolved by improvements in nanopore basecalling models.
Molecular Pathogenesis of Cholestasis
Authors: Michael Trauner, Peter J. Meier, James L. Boyer
Journal: New England Journal of Medicine (1998)

The formation of bile is a vital function, and its impairment by drugs or infectious, autoimmune, metabolic, or genetic disorders results in the syndrome commonly known as cholestasis.1 The secretion of bile normally depends on the function of a number of membrane transport systems in hepatocytes and bile-duct epithelial cells (cholangiocytes) and on the structural and functional integrity of the bile-secretory apparatus. This review summarizes the molecular defects in hepatocellular membrane transporters that are associated with various forms of cholestatic liver disease in humans.Molecular Mechanisms of Bile FormationBile formation is an osmotic secretory process that is driven by . . .
Waning of antibody levels induced by a 13-valent pneumococcal conjugate vaccine, using a 3 + 0 schedule, within the first year of life among children younger than 5 years in Blantyre, Malawi: an observational, population-level, serosurveillance study
Authors: Todd D Swarthout, Marc Y R Henrion, Deus Thindwa, James E Meiring, Maurice Mbewe, Akuzike Kalizang’Oma, Comfort Brown, Jacquline Msefula, Brewster Moyo, Andrew A Mataya, Susanne Barnaba, Emma Pearce, Melita Gordon, David Goldblatt, Neil French, Robert S Heyderman
Journal: The Lancet Infectious Diseases (2022)

Pneumococcal conjugate vaccines (PCVs) induce serotype-specific IgG antibodies, effectively reducing vaccine-serotype carriage and invasive pneumococcal disease (IPD). IgG production wanes approximately 1 month after vaccination in absence of serotype-specific exposure. With uncertainty surrrounding correlate of protection (CoP) estimates and with persistent vaccine-serotype carriage and vaccine-serotype IPD after PCV13 introduction, we aimed to profile population-level immunogenicity among children younger than 5 years in Blantyre, Malawi.
Bloodstream infections caused by Enterobacter hormaechei ST133 in China, 2010–22
Authors: Kai Zhou, Yanzi Zhou, Chun-Xu Xue, Tingting Xu, Yunbo Chen, Ping Shen, Yonghong Xiao
Journal: The Lancet Microbe (2022)

Enterobacter cloacae complex (ECC) is composed of multiple species and is conventionally regarded as a low-virulence pathogen, often causing infections in immunocompromised patients admitted to adult, paediatric, and neonatal intensive care units.1 However, interspecies diversities of pathogenicity have been noted in a few studies.2,3 Enterobacter bugandensis was identified as a hypervirulent species of ECC responsible for fatal septic shock of newborn babies in France.2 In 2022, we reported an epidemic hypervirulent clone of Enterobacter hormaechei, sequence type (ST) 133, showing high invasiveness and mortality in clinical settings.
Transmission of SARS-CoV-2 by children to contacts in schools and households: a prospective cohort and environmental sampling study in London
Authors: Rebecca Cordery, Lucy Reeves, Jie Zhou, Aileen Rowan, Patricia Watber, Carolina Rosadas, Michael Crone, Marko Storch, Paul Freemont, Lucy Mosscrop, Alice Cowley, Gina Zelent, Kate Bisset, Holly Le Blond, Sadie Regmi, Christian Buckingham, Ramlah Junaideen, Nadia Abdulla, Joseph Eliahoo, Miranda Mindlin, Theresa Lamagni, Wendy Barclay, Graham P Taylor, Shiranee Sriskandan
Journal: The Lancet Microbe (2022)
Lung epithelial and myeloid innate immunity in influenza-associated or COVID-19-associated pulmonary aspergillosis: an observational study
Authors: Simon Feys, Samuel M Gonçalves, Mona Khan, Sumin Choi, Bram Boeckx, Denis Chatelain, Cristina Cunha, Yves Debaveye, Greet Hermans, Marjan Hertoghs, Stephanie Humblet-Baron, Cato Jacobs, Katrien Lagrou, Lukas Marcelis, Julien Maizel, Philippe Meersseman, Rémy Nyga, Laura Seldeslachts, Marick Rodrigues Starick, Karin Thevissen, Christophe Vandenbriele, Lore Vanderbeke, Greetje Vande Velde, Niels Van Regenmortel, Arno Vanstapel, Sam Vanmassenhove, Alexander Wilmer, Frank L Van De Veerdonk, Gert De Hertogh, Peter Mombaerts, Diether Lambrechts, Agostinho Carvalho, Johan Van Weyenbergh, Joost Wauters
Journal: The Lancet Respiratory Medicine (2022)
An Algorithm for the Operational Assessment of Adverse Drug Reactions
Authors: Michael S. Kramer
Journal: JAMA (1979)

Despite widespread clinical and epidemiologic attention to adverse drug reactions (ADRs), their clinical identification has been a nonreproducible act of unspecified subjective judgment; adequate operational criteria have not been available for diagnostic decisions about the cause of an observed untoward clinical manifestation. To improve scientific precision in the diagnosis of ADRs, we have developed an algorithm that provides detailed operational criteria for ranking the probability of causation when ADR is suspected between a drug and a clinical manifestation. The algorithm provides a scoring system for six axes of decision strategy: previous general experience with the drug, alternative etiologic candidates, timing of events, drug levels and evidence of overdose, dechallenge, and rechallenge. The sum of the scores is ordinally partitioned to rate the candidate ADR as definite, probable, possible, or unlikely. (<i>JAMA</i>242:623-632, 1979)
Anterior Sacral Meningocele
Authors: Frank M. Anderson
Journal: JAMA (1977)

Anterior sacral meningoceles are congenital lesions that consist of a spinal fluid-filled sac in the pelvis communicating by a small neck with the spinal subarachnoid space through a defect in the sacrum. The three patients with this disorder presented here had characteristic symptoms and physical findings: chronic constipation, a pelvic mass, and almost unmistakable roentgenographic changes, but diagnosis was delayed from 11 months to 21 years in all three. After prolonged and complicated treatment, the primary lesions have been surgically eradicated and function is generally satisfactory. (<i>JAMA</i>237:39-42, 1977)
Inhibition of Nuclear Translocation of Nuclear Factor-κB Contributes to 3,3′-Diindolylmethane-Induced Apoptosis in Breast Cancer Cells
Authors: KM Wahidur Rahman, Fazlul H. Sarkar
Journal: Cancer Research (2005)

Abstract Dietary indole-3-carbinol (I3C), a natural compound present in vegetables of the genus Brassica, showed clinical benefits and caused apoptosis in breast cancer cells. Our laboratory and others have shown that I3C induces apoptosis in breast cancer cells mediated by inactivation of Akt and nuclear factor-κB (NF-κB) pathway. 3,3′-Diindolylmethane (DIM), a major in vivo acid-catalyzed condensation product of I3C, also showed some benefit in breast cancer. However, the precise molecular mechanism(s) by which DIM induces apoptosis in breast cancer cells has not been fully elucidated. Hence, we investigated whether DIM-induced apoptosis of breast cancer cells could also be mediated by inactivation of Akt and NF-κB. We found that DIM induces apoptotic processes in MCF10A derived malignant (MCF10CA1a) cell lines but not in nontumorigenic parental MCF10A cells. DIM specifically inhibits Akt kinase activity and abrogates the epidermal growth factor–induced activation of Akt in breast cancer cells, similar to those observed for I3C. We also found that DIM reduces phosphorylation of IκBα, an inhibitor of NF-κB. Our confocal microscopy study clearly showed that DIM blocks the translocation of p65, a subunit of NF-κB to the nucleus. DNA binding analysis and transfection studies with IκB kinase cDNA revealed that overexpression of IκB kinase mediates IκBα phosphorylation, which activates NF-κB, and this activation was completely abrogated by DIM treatment. Taken together, these results showed for the first time that the inactivation of Akt and NF-κB activity also plays important roles in DIM-induced apoptosis in breast cancer cells, which seems to be more relevant to in vivo situations.
Association of respiratory symptoms and lung function with occupation in the multinational Burden of Obstructive Lung Disease (BOLD) study
Authors: Jate Ratanachina, Andre F.S. Amaral, Sara De Matteis, Herve Lawin, Kevin Mortimer, Daniel O. Obaseki, Imed Harrabi, Meriam Denguezli, Emiel F.M. Wouters, Christer Janson, Rune Nielsen, Amund Gulsvik, Hamid Hacene Cherkaski, Filip Mejza, Padukudru Anand Mahesh, Asma Elsony, Rana Ahmed, Wan Tan, Li Cher Loh, Abdul Rashid, Michael Studnicka, Asaad A. Nafees, Terence Seemungal, Althea Aquart-Stewart, Mohammed Al Ghobain, Jinping Zheng, Sanjay Juvekar, Sundeep Salvi, Rain Jogi, David Mannino, Thorarinn Gislason, A. Sonia Buist, Paul Cullinan, Peter Burney
Journal: European Respiratory Journal (2022)

Chronic obstructive pulmonary disease has been associated with exposures in the workplace. We aimed to assess the association of respiratory symptoms and lung function with occupation in the Burden of Obstructive Lung Disease study.We analysed cross-sectional data from 28 823 adults (≥40 years) in 34 countries. We considered 11 occupations and grouped them by likelihood of exposure to organic dusts, inorganic dusts and fumes. The association of chronic cough, chronic phlegm, wheeze, dyspnoea, forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1)/FVC with occupation was assessed, per study site, using multivariable regression. These estimates were then meta-analysed. Sensitivity analyses explored differences between sexes and gross national income.Overall, working in settings with potentially high exposure to dusts or fumes was associated with respiratory symptoms but not lung function differences. The most common occupation was farming. Compared to people not working in any of the 11 considered occupations, those who were farmers for ≥20 years were more likely to have chronic cough (OR 1.52, 95% CI 1.19-1.94), wheeze (OR 1.37, 95% CI 1.16-1.63) and dyspnoea (OR 1.83, 95% CI 1.53-2.20), but not lower FVC (β=0.02 L, 95% CI -0.02-0.06 L) or lower FEV1/FVC (β=0.04%, 95% CI -0.49-0.58%). Some findings differed by sex and gross national income.At a population level, the occupational exposures considered in this study do not appear to be major determinants of differences in lung function, although they are associated with more respiratory symptoms. Because not all work settings were included in this study, respiratory surveillance should still be encouraged among high-risk dusty and fume job workers, especially in low- and middle-income countries.
Utility of whole genome sequencing in assessing risk and clinically relevant outcomes for pulmonary fibrosis
Authors: David Zhang, Chad A. Newton, Binhan Wang, Gundula Povysil, Imre Noth, Fernando J. Martinez, Ganesh Raghu, David Goldstein, Christine Kim Garcia
Journal: European Respiratory Journal (2022)

Whole genome sequencing (WGS) can detect variants and estimate telomere length. The clinical utility of WGS in estimating risk, progression and survival of pulmonary fibrosis patients is unknown.In this observational cohort study, we performed WGS on 949 patients with idiopathic pulmonary fibrosis or familial pulmonary fibrosis to determine rare and common variant genotypes, estimate telomere length and assess the association of genomic factors with clinical outcomes.WGS estimates of telomere length correlated with quantitative PCR (R=0.65) and Southern blot (R=0.71) measurements. Rare deleterious qualifying variants were found in 14% of the total cohort, with a five-fold increase in those with a family history of disease versus those without (25% versus 5%). Most rare qualifying variants (85%) were found in telomere-related genes and were associated with shorter telomere lengths. Rare qualifying variants had a greater effect on telomere length than a polygenic risk score calculated using 20 common variants previously associated with telomere length. The common variant polygenic risk score predicted telomere length only in sporadic disease. Reduced transplant-free survival was associated with rare qualifying variants, shorter quantitative PCR-measured telomere lengths and absence of the MUC5B promoter (rs35705950) single nucleotide polymorphism, but not with WGS-estimated telomere length or the common variant polygenic risk score. Disease progression was associated with both measures of telomere length (quantitative PCR measured and WGS estimated), rare qualifying variants and the common variant polygenic risk score.As a single test, WGS can inform pulmonary fibrosis genetic-mediated risk, evaluate the functional effect of telomere-related variants by estimating telomere length, and prognosticate clinically relevant disease outcomes.
Gut microbiota mediate vascular dysfunction in a murine model of sleep apnoea: effect of probiotics
Authors: Mohammad Badran, Abdelnaby Khalyfa, Aaron C. Ericsson, Clementine Puech, Zachary McAdams, Shawn B. Bender, David Gozal
Journal: European Respiratory Journal (2022)

Obstructive sleep apnoea (OSA) is a chronic prevalent condition characterised by intermittent hypoxia (IH), and is associated with endothelial dysfunction and coronary artery disease (CAD). OSA can induce major changes in gut microbiome diversity and composition, which in turn may induce the emergence of OSA-associated morbidities. However, the causal effects of IH-induced gut microbiome changes on the vasculature remain unexplored. Our objective was to assess if vascular dysfunction induced by IH is mediated through gut microbiome changes.